A variety of attempts have been made to replace or supplement the function of failing mammalian organs with artificial organs. In bioartificial organs, actual organ tissue or cells are incorporated into the artificial device and the device is located in vivo in a situation such that the organ tissue or cells are exposed as much as possible to normal physiological signals.
In a typical bioartificial organ, the transplanted tissue is protected against immune rejection by a semi-permeable membrane permeable to nutrients, oxygen, stimulating molecules and the secreted active molecules but not to immunoglobulins. Because the semi-permeable membrane prevents an attack by the immune system, tissue from other species can be used, thus allowing for an almost unlimited source of tissue. In addition, immunosuppressant drugs are not necessary. The porosity of the membrane must be adjusted to selectivity allow the passage of the suitable molecules but not immunoglobulins. This can be achieved with membranes having a molecular weight cut off inferior to 100,000 daltons which excludes larger molecules such as immunoglobulins (&gt;160,000 daltons).
This approach is applicable for the treatment of various illnesses such as hemophilia, hypoparathyroidism, Parkinson's disease, Huntington's disease and hepatic failure.
One disease which has been the focus of this approach is diabetes, a disease caused by the destruction of the insulin-secreting .beta. cells of the Islets of Langerhans in the pancreas and affecting about 30 million people worldwide.
The usual therapy for diabetes is daily insulin injections during the entire life of the patient. As well as being a cumbersome therapy, insulin injections do not achieve optimal control of glycemia. It is thought that the long-term complications of diabetes, which occur even with insulin therapy, are related to this imperfect control of glycemia.
If insulin could be supplied to a diabetic patient by living .beta. cells which are capable of responding in a finely tuned manner, so as to keep blood sugar within normal limits, an improved outlook for diabetic patients could be expected.
Various attempts have been made to incorporate islet cells into an artificial pancreas device or bioartificial pancreas.
Healthy islet cells are separated from host tissues in such devices by a semi-permeable membrane which is permeable to glucose and insulin but not to cells or immunoglobulins. This protection of the islet graft by the membrane eliminates the need for immunosuppression of the patient.
Another benefit derived from the use of the membrane is that it allows for the use of xenogeneic islets, such as porcine islets, thus reducing the problem of the limited availability of transplantable human pancreatic tissue.
Bioartificial pancreases can be divided into two groups: the first group comprises extravascular systems, where there is no contact between the protective membrane and blood of the patient. The second group comprises vascular systems where the blood of the patient circulates in contact with the membrane.
One example of the second group is the bioartificial pancreas described by Lapeintre, J. et al., (1990), Artificial Organs, v. 14, pp. 20-27. This device is U-shaped in design and is connected to an arteriovenous shunt.
Glucose and insulin transfer through the membrane is achieved in this device by two types of flux; a flux by diffusion caused by the glucose and insulin concentration gradients between the blood and the islet compartment, and a flux by ultrafiltration caused by the difference of pressure between the upper blood channel and the lower blood channel of the device. This difference of pressure is achieved by the resistance to blood flow in a small diameter U-shaped tube connecting the two blood channels. Therefore, in this system, a resistance to flow is required to obtain an ultrafiltration flux. However, this resistance to flow creates serious blood clotting problems in this device, making the device unsuitable for in vivo implantation.
In order to avoid blood clotting, the blood flow through the device should be without any resistance to flow. In addition, the blood channels of this device are designed as flat, rectangular chambers with grooved passages, which is not a desirable design for use with blood. These channels should preferably be designed so as to avoid turbulence and stasis of the blood flow.
These problems have been overcome by the bioartificial organ of the present invention which utilizes the natural pressure difference between artery and vein (.about.80 to 90 mm Hg), to create a large ultrafiltration flux through the islet chamber, instead of using a pressure difference artificially induced by creating a large resistance to blood flow. In addition, this new device minimizes the extent of artificial surface in contact with blood and does not introduce resistance or disruption in the blood flow that would induce the turbulence responsible for blood clotting.